Lipid A, the hydrophobic anchor of bacterial endotoxin is not only an essential component of the outer membrane of Gram-negative bacteria, but it is also one of the most potent small molecule elicitors of the eukaryotic innate immune response. Indeed, so important is its role in innate immunity that humans have evolved multiple proteins with the capacity for high-affinity recognition of this glycolipid, including LBP, CD14, the TLR4-MD2 complex, caspase 4, and caspase 5. Notwithstanding impressive advances in total synthesis of this complex molecule, the availability of facile methods to prepare structurally defined analogs of this family of natural products remains a major roadblock in our understanding of their remarkable biological properties. Here we present a fundamentally novel approach to access these structure-activity relationships.